Cesium carbonate → 1-({1-[2-(Bicyclo[3.1.0]hex-3-yloxycarbonylamino)-3,3-dimethylbutyryl]-4-[8-chloro-7-(2,2-dimethoxyethoxy)-2-(2-isopropylaminothiazol-4-yl)-quinolin-4-yloxy]pyrrolidine-2-carbonyl}amino)-2-ethylcyclopropanecarboxylic acid methyl ester

HRID 1893699Notes

Reaction equation

HRID 1893699 reaction equation
[CH3:1][O:2][C:3]([C:5]1([NH:10][C:11]([CH:13]2[CH2:17][CH:16](OS(C3C=CC(Br)=CC=3)(=O)=O)[CH2:15][N:14]2[C:29](=[O:45])[CH:30]([NH:35][C:36]([O:38][CH:39]2[CH2:44][CH:43]3[CH:41]([CH2:42]3)[CH2:40]2)=[O:37])[C:31]([CH3:34])([CH3:33])[CH3:32])=[O:12])[CH2:7][CH:6]1[CH2:8][CH3:9])=[O:4].[Cl:46][C:47]1[C:48]([O:67][CH2:68][CH:69]([O:72][CH3:73])[O:70][CH3:71])=[CH:49][CH:50]=[C:51]2[C:56]=1[N:55]=[C:54]([C:57]1[N:58]=[C:59]([NH:62][CH:63]([CH3:65])[CH3:64])[S:60][CH:61]=1)[CH:53]=[C:52]2[OH:66].C(=O)([O-])[O-].[Cs+].[Cs+].[Li+].[Cl-]>CN1C(=O)CCC1.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1([NH:10][C:11]([CH:13]2[CH2:17][CH:16]([O:66][C:52]3[C:51]4[C:56](=[C:47]([Cl:46])[C:48]([O:67][CH2:68][CH:69]([O:70][CH3:71])[O:72][CH3:73])=[CH:49][CH:50]=4)[N:55]=[C:54]([C:57]4[N:58]=[C:59]([NH:62][CH:63]([CH3:65])[CH3:64])[S:60][CH:61]=4)[CH:53]=3)[CH2:15][N:14]2[C:29](=[O:45])[CH:30]([NH:35][C:36]([O:38][CH:39]2[CH2:44][CH:43]3[CH:41]([CH2:42]3)[CH2:40]2)=[O:37])[C:31]([CH3:33])([CH3:34])[CH3:32])=[O:12])[CH2:7][CH:6]1[CH2:8][CH3:9])=[O:4]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 433294Lithium ChlorideHCID 766050501-{[1-[2-(Bicyclo[3.1.0]hex-3-yloxycarbonylamino)-3,3-dimethyl-butyryl]-4-(4-bromobenzenesulfonyloxy)pyrrolidine-2-carbonyl]amino}-2-ethyl-cyclopropanecarboxylic acid methyl esterHCID 178496098HCID 178496098, compound

Product 1

HCID 766049481-({1-[2-(Bicyclo[3.1.0]hex-3-yloxycarbonylamino)-3,3-dimethylbutyryl]-4-[8-chloro-7-(2,2-dimethoxyethoxy)-2-(2-isopropylaminothiazol-4-yl)-quinolin-4-yloxy]pyrrolidine-2-carbonyl}amino)-2-ethylcyclopropanecarboxylic acid methyl esterYield 75%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
65 °C

Procedure

To a mixture of 1-{[1-[2-(bicyclo[3.1.0]hex-3-yloxycarbonylamino)-3,3-dimethyl-butyryl]-4-(4-bromobenzenesulfonyloxy)pyrrolidine-2-carbonyl]amino}-2-ethyl-cyclopropanecarboxylic acid methyl ester (15 g, 35 mmol) and 8-chloro-7-(2,2-dimethoxyethoxy)-2-(2-isopropylaminothiazol-4-yl)-quinolin-4-ol (27.5 g, 38.5 mmol) in NMP (200 ml) was added cesium carbonate (25.1 g, 77 mmol). The mixture was stirred at 65° C. for 5 h. The reaction was cooled to room temperature and EtOAc (600 ml) and an aqueous solution of 3% LiCl (600 ml) were added to the mixture. The organic layer was washed with aqueous 3% LiCl (1×600 ml), brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography to produce 1-({1-[2-(bicyclo[3.1.0]hex-3-yloxycarbonylamino)-3,3-dimethylbutyryl]-4-[8-chloro-7-(2,2-dimethoxyethoxy)-2-(2-isopropylaminothiazol-4-yl)-quinolin-4-yloxy]pyrrolidine-2-carbonyl}amino)-2-ethylcyclopropanecarboxylic acid methyl ester as a yellow solid (23.6 g, 75% yield). LCMS found 900.1 [M+H]+.

Workup

  1. temperatureThe reaction was cooled to room temperature
  2. washThe organic layer was washed with aqueous 3% LiCl (1×600 ml), brine
  3. dry with materialdried (Na2SO4)
  4. concentrationconcentrated in vacuo
  5. customThe residue was purified by silica gel chromatography

Sources & evidence

ORD record
ord-241e49750c9e4ff4bbe9d556d652c308
Source dataset
uspto-grants-2013_08
Patent number
US08513186B2

Reaction notes

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